Prostate-specific membrane antigen antibody drug conjugates

Abstract

This invention relates to prostate-specific membrane antigen (PSMA) antibodies and antibody drug conjugates comprising at least one non-naturally-encoded amino acid. Disclosed herein are αPSMA antibodies with one or more non-naturally encoded amino acids and further disclosed are antibody drug conjugates wherein the αPSMA antibodies of the invention are conjugated to one or more toxins. Also disclosed herein are non-natural amino acid dolastatin analogs that are further modified post-translationally, methods for effecting such modifications, and methods for purifying such dolastatin analogs. Typically, the modified dolastatin analogs include at least one oxime, carbonyl, dicarbonyl, and/or hydroxylamine group. Further disclosed are methods for using such non-natural amino acid antibody drug conjugates, dolastatin analogs, and modified non-natural amino acid dolastatin analogs, including therapeutic, diagnostic, and other biotechnology uses.

What is claimed is: 
     
         1 . A compound comprising Formula (VIII) or (IX): 
       
         
           
           
               
               
           
         
         wherein:
 A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; 
 B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, —N(R′)—N═, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N—N═, —C(R′) 2 —N═N—, and —C(R′) 2 —N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl; 
 R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; 
 R 1  is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
 R 2  is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
 R 3  and R 4  are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R 3  and R 4  or two R 3  groups optionally form a cycloalkyl or a heterocycloalkyl; 
 Z has the structure of: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 5  is H, COR 8 , C 1 -C 6 alkyl, or thiazole;
 R 8  is OH; 
 
             R 6  is OH or H; 
             Ar is phenyl or pyridine; 
           
           R 7  is C 1 -C 6 alkyl or hydrogen; 
           L is a linker selected from the group consisting of -alkylene-, -alkylene-C(O)—, -(alkylene-O) n -alkylene -, -(alkylene-O) n -alkylene-C(O)—, -(alkylene-O) n —(CH 2 ) n′ —NHC(O)—(CH 2 ) n″ —C(Me) 2 -S—S—(CH 2 ) n″′ , —NHC(O)-(alkylene-O) n″″ -alkylene-, -(alkylene-O) n , alkylene-W—, -alkylene-C(O)—W—, -(alkylene-O) n -alkylene-U-alkylene-C(O)—, and -(alkylene-O) n -alkylene-U-alkylene-;
 W has the structure of: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             U has the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              and 
             each n, n′, n″, n′″ and n″″ are independently integers greater than or equal to one; 
           
         
         or an active metabolite, or a pharmaceutically acceptable prodrug or solvate thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is a polypeptide. 
     
     
         3 . The compound of  claim 2 , wherein the polypeptide is an antibody. 
     
     
         4 . The compound of  claim 3 , wherein the antibody is an anti-prostate-specific membrane antigen (αPSMA) antibody. 
     
     
         5 . The compound of  claim 4 , wherein the αPSMA antibody comprises one or more non-naturally encoded amino acids. 
     
     
         6 . The compound of  claim 4 , wherein the αPSMA antibody comprises at least one and no more than ten non-naturally encoded amino acids. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is a polypeptide. 
     
     
         8 . The compound of  claim 7 , wherein the polypeptide is an antibody. 
     
     
         9 . The compound of  claim 8 , wherein the antibody is an αPSMA antibody. 
     
     
         10 . The compound of  claim 9 , wherein the αPSMA antibody comprises one or more non-naturally encoded amino acids. 
     
     
         11 . The compound of  claim 9 , wherein the αPSMA antibody comprises at least one and no more than ten non-naturally encoded amino acids. 
     
     
         12 . The compound, or salt thereof, comprising Formula (X), (XI), (XII) or (XIII): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 A is optional, and when present is lower alkylene, substituted lower alkylene, lower cycloalkylene, substituted lower cycloalkylene, lower alkenylene, substituted lower alkenylene, alkynylene, lower heteroalkylene, substituted heteroalkylene, lower heterocycloalkylene, substituted lower heterocycloalkylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; 
 B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, lower heteroalkylene, substituted lower heteroalkylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, —N(R′)—N═, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N—N═, —C(R′) 2 —N═N—, and —C(R′) 2 —N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl; 
 R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; 
 R 1  is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
 R 2  is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
 R 3  and R 4  are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R 3  and R 4  or two R 3  groups optionally form a cycloalkyl or a heterocycloalkyl; 
 Z has the structure of: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 5  is H, CO 2 H, C 1 -C 6 alkyl, or thiazole; 
             R 6  is OH or H; 
             Ar is phenyl or pyridine; 
           
           R 7  is C 1 -C 6 alkyl or hydrogen; 
           L 1 , L 2 , L 3 , and L 4  are each linkers independently selected from the group consisting of a bond, -alkylene-, -(alkylene-O) n -alkylene-J-, -alkylene′-J-(alkylene-O) n -alkylene-, -J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-(alkylene-O) n ′-alkylene-J′-, -(alkylene-O) n -alkylene-J-alkylene′-, —W—, -alkylene-W—, alkylene′-J-(alkylene-NMe) n -alkylene-W—, -J-(alkylene-NMe) n -alkylene-W—, -J-alkylene-NMe-alkylene′-NMe-alkylene″-W—, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene″′-W—;
 W has the structure of: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             each J and J′ independently have the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
              and 
             each n and n′ are independently integers greater than or equal to one. 
           
         
       
     
     
         13 . The compound of  claim 12 , wherein R 1  is a polypeptide. 
     
     
         14 . The compound of  claim 13 , wherein the polypeptide is an antibody. 
     
     
         15 . The compound of  claim 14 , wherein the antibody is an αPSMA antibody. 
     
     
         16 . The compound of  claim 12 , wherein R 2  is a polypeptide. 
     
     
         17 . The compound of  claim 16 , wherein the polypeptide is an antibody. 
     
     
         18 . The compound of  claim 17 , wherein the antibody is an αPSMA antibody. 
     
     
         19 . A method for derivatizing a dolastatin analog comprising Formula (I), (III), (IV), (V), or (VI), the method comprising contacting the dolastatin analog with a reagent of Formula (XXXVII), wherein Formula (I), (III), (IV), (V), or (VI) correspond to: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 Z has the structure of: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 5  is H, COR 8 , C 1 -C 6 alkyl, or thiazole;
 R 8  is OH or —NH-(alkylene-O) n —NH 2 ; 
 
             R 6  is OH or H; 
             Ar is phenyl or pyridine; 
           
           R 7  is C 1 -C 6  alkyl or hydrogen; 
           Y is NH 2 —O— or methyl; 
           L, L 1 , L 2 , L 3 , and L 4  are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-C(O)—, -(alkcylene-O) n —(CH 2 ) n′ —HC(O)—(CH 2 ) n″ —C(Me) 2 -S—S—(CH 2 ) n″′ —NHC(O)-(alkylene-O) n″″ -alkylene-, -(alkylene-O) n -alkylene-W—, -alkylene-C(O)—W—, -(alkylene-O) n -alkylene-J-, -alkylene′-J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-alkylene′, J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-(alkylene-O) n ′-alkylene-J′-, —W—, -alkylene-W—, alkylene′-J-(alkylene-NMe) n -alkylene-W—, and J-(alkylene-NMe) n -alkylene-W—, -(alkylene-O) n -alkylene-U-alkylene-C(O)-(alkylene-O) n -alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W—, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene″′-W—;
 W has the structure of: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             U has the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             each J and J′ independently have the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             or L is absent, Y is methyl, R 5  is COR 8 , and R 8  is —NH-(alkylene-O) n —NH 2 ; and 
             each n, n′, n″, n″′ and n″″ are independently integers greater than or equal to one; 
           
         
         wherein Formula (XXXVII) corresponds to: 
       
       
         
           
           
               
               
           
         
         wherein:
 A is optional, and when present is lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, arylene, substituted arylene, heteroarylene, substituted heteroarylene, alkarylene, substituted alkarylene, aralkylene, or substituted aralkylene; 
 B is optional, and when present is a linker selected from the group consisting of lower alkylene, substituted lower alkylene, lower alkenylene, substituted lower alkenylene, —O—, —O-(alkylene or substituted alkylene)-, —S—, —S-(alkylene or substituted alkylene)-, —S(O) k — where k is 1, 2, or 3, —S(O) k (alkylene or substituted alkylene)-, —C(O)—, —C(O)-(alkylene or substituted alkylene)-, —C(S)—, —C(S)-(alkylene or substituted alkylene)-, —N(R′)—, —NR′-(alkylene or substituted alkylene)-, —C(O)N(R′)—, —CON(R′)-(alkylene or substituted alkylene)-, —CSN(R′)—, —CSN(R′)-(alkylene or substituted alkylene)-, —N(R′)CO-(alkylene or substituted alkylene)-, —N(R′)C(O)O—, —S(O) k N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(S)N(R′)—, —N(R′)S(O) k N(R′)—, —N(R′)—N═, —C(R′)═N—, —C(R′)═N—N(R′)—, —C(R′)═N—N═, —C(R′) 2 —N═N—, and —C(R′) 2 —N(R′)—N(R′)—, where each R′ is independently H, alkyl, or substituted alkyl;
 each R′ is independently H, alkyl, or substituted alkyl; 
 
 K is 
 
       
       
         
           
           
               
               
           
         
         
           R is H, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; 
           R 1  is H, an amino protecting group, resin, at least one amino acid, or polynucleotide; 
           R 2  is OH, an ester protecting group, resin, at least one amino acid, or polynucleotide; and 
           R 3  and R 4  are each independently H, halogen, lower alkyl, or substituted lower alkyl, or R 3  and R 4  or two R 3  groups optionally form a cycloalkyl or a heterocycloalkyl. 
         
       
     
     
         20 . The method of  claim 19 , wherein the derivatized dolastatin analog comprises at least one oxime containing amino acid having the structure of Formula (VIII), (IX), (X), (XI), (XII), or (XIII): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 19 , wherein the dolastatin analog is contacted with the reagent of Formula (XXXVII) in aqueous solution under mildly acidic conditions. 
     
     
         22 . A compound comprising Formula (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), or (XXX): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 Z has the structure of: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 5  is H, CO 2 H, C 1 -C 6 alkyl, or thiazole; 
             R 6  is OH or H; 
             Ar is phenyl or pyridine; 
           
           R 1  is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
           R 2  is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
           R 4  is H, halogen, lower alkyl, or substituted lower alkyl; 
           R 7  is C 1 -C 6 alkyl or hydrogen; 
           L, L 1 , L 2 , L 3 , and L 4  are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -alkylene-J-, -(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-C(O)—, -(alkylene-O) n -J-, -(alkylene-O) n -J-alkylene-, -(alkylene-O) n —(CH 2 ) n  NHC(O)—(CH 2 ) n″ —C(Me) 2 -S—S—(CH 2 ) n″′ —NHC(O)-(alkylene-O) n″″ -alkylene-, -(alkylene-O)i-alkylene-W—, -alkylene-C(O)—W—, -(alkylene-O) n -alkylene-J-, -alkylene′-J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-alkylene′, -J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-(alkylene-O) n ′-alkylene-J′-, —W—, -alkylene-W—, alkylene′-J-(alkylene-NMe) n -alkylene-W—, -J-(alkylene-NMe) n -alkylene-W—, -(alkylene-O) n -alkylene-U-alkylene-C(O)—, -(alkylene-O) n -alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W—, and -alkylene-J-alkylene′-NMe-alkylene″-NMe-alkylene″′-W—;
 W has the structure of: 
 
         
       
       
         
           
           
               
               
           
         
         
           
             U has the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             each J and J′ independently have the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             each n and n′ are independently integers greater than or equal to one; and 
           
           each R 16  is independently selected from the group consisting of hydrogen, halogen, alkyl, NO 2 , CN, and substituted alkyl. 
         
       
     
     
         23 . The compound of  claim 22 , wherein R 1  is a polypeptide. 
     
     
         24 . The compound of  claim 23 , wherein the polypeptide is an antibody. 
     
     
         25 . The compound of  claim 24 , wherein the antibody is an αPSMA antibody. 
     
     
         26 . The compound of  claim 22 , wherein R 2  is a polypeptide. 
     
     
         27 . The compound of  claim 26 , wherein the polypeptide is an antibody. 
     
     
         28 . The compound of  claim 27 , wherein the antibody is an αPSMA antibody. 
     
     
         29 . A compound comprising Formula (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 Z has the structure of: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 5  is H, CO 2 H, C 1 -C 6 alkyl, or thiazole; 
             R 6  is OH or H; 
             Ar is phenyl or pyridine; 
           
           R 1  is H, an amino protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
           R 2  is OH, an ester protecting group, resin, at least one amino acid, polypeptide, or polynucleotide; 
           R 4  is H, halogen, lower alkyl, or substituted lower alkyl; 
           R 7  is C 1 -C 6 alkyl or hydrogen; 
           L, L 1 , L 2 , L 3 , and L 4  are each linkers selected from the group consisting of a bond, -alkylene-, -alkylene-C(O)—, -alkylene-J-, -(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-C(O)—, -(alkylene-O) n -J-, -(alkylene-O) n -J-alkylene-, -(alkylene-O) n —(CH 2 ) n′ —NHC(O)—(CH 2 ) n″ —C(Me) 2 -S—S—(CH 2 ) n″′ —NHC(O)-(alkylene-O) n″″ -alkylene, -(alkylene-O) n -alkylene-W—, -alkylene-C(O)—W—, -(alkylene-O) n -alkylene-J-, -alkylene′-J-(alkylene-O) n -alkylene-, -(alkylene-O) n -alkylene-J-alkylene′, -J-(alkylene-O) n -alkylene, -(alkylene-O) n -alkylene-J-(alkylene-O) n ′-alkylene-J′-, —W—, -alkylene-W—, alkylene′-J-(alkylene-NMe) n -alkylene-W—, -J-(alkylene-NMe) n -alkylene-W—, -(alkylene-O) n -alkylene-U-alkylene-C(O)—, -(alkylene-O) n -alkylene-U-alkylene-; -J-alkylene-NMe-alkylene′-NMe-alkylene″-W—, and -alkylene -J-alkylene′-NMe-alkylene″-NMe-alkylene″′-W—; 
         
       
       
         
           
           
               
               
           
         
         
           
             U has the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             each J and J independently have the structure of: 
           
         
       
       
         
           
           
               
               
           
         
         
           
             each n and n′ are independently integers greater than or equal to one; 
           
           D has the structure of: 
         
       
       
         
           
           
               
               
           
         
         
           
             each R 17  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylalkoxy, substituted alkylalkoxy, polyalkylene oxide, substituted polyalkylene oxide, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, -(alkylene or substituted alkylene)-ON(R″) 2 , -(alkylene or substituted alkylene)-C(O)SR″, -(alkylene or substituted alkylene)-S—S-(aryl or substituted aryl), —C(O)R″, —C(O) 2 R″, or —C(O)N(R″) 2 , wherein each R″ is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; 
             each Z 1  is a bond, CR 17 R 17 , O, S, NR′, CR 17 R 17 —CR 17 R 17 , CR 17 R 17 —O, O—CR 17 R 17 , CR 17 R 17 —S, S—CR 17 R 17 , CR 17 R 17 —NR′, or NR′—CR 17 R 17 ;
 each R′ is H, alkyl, or substituted alkyl; 
 
             each Z 2  is selected from the group consisting of a bond, —C(O)—, —C(S)—, optionally substituted C 1 -C 3  alkylene, optionally substituted C 1 -C 3  alkenylene, and optionally substituted heteroalkyl; 
             each Z 3  are independently selected from the group consisting of a bond, optionally substituted C 1 -C 4  alkylene, optionally substituted C 1 -C 4  alkenylene, optionally substituted heteroalkyl, —O—, —S—, —C(O)—, —C(S)—, and —N(R′)—; 
             each T 3  is a bond, C(R″)(R″), O, or S; with the proviso that when T 3  is O or S, R″ cannot be halogen; 
             each R″ is H, halogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; 
             m and p are 0, 1, 2, or 3, provided that at least one of m or p is not 0; 
             M 2  is 
           
         
       
       
         
           
           
               
               
           
         
         
           
              where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; 
             M 3  is 
           
         
       
       
         
           
           
               
               
           
         
         
           
              where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; 
             M 4  is 
           
         
       
       
         
           
           
               
               
           
         
         
           
              where (a) indicates bonding to the B group and (b) indicates bonding to respective positions within the heterocycle group; 
             each R 19  is independently selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkoxy, ester, ether, thioether, aminoalkyl, halogen, alkyl ester, aryl ester, amide, aryl amide, alkyl halide, alkyl amine, alkyl sulfonic acid, alkyl nitro, thioester, sulfonyl ester, halosulfonyl, nitrile, alkyl nitrite, and nitro; 
             q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; and 
           
           each R 16  is independently selected from the group consisting of hydrogen, halogen, alkyl, NO 2 , CN, and substituted alkyl. 
         
       
     
     
         30 . The compound of  claim 29 , wherein R 1  is a polypeptide. 
     
     
         31 . The compound of  claim 30 , wherein the polypeptide is an antibody. 
     
     
         32 . The compound of  claim 31 , wherein the antibody is an PSMA antibody. 
     
     
         33 . The compound of  claim 29 , wherein R 2  is a polypeptide. 
     
     
         34 . The compound of  claim 33 , wherein the polypeptide is an antibody. 
     
     
         35 . The compound of  claim 34 , wherein the antibody is an αPSMA antibody. 
     
     
         36 . The compound of  claim 29 , comprising Formula (XXXI-A): 
       
         
           
           
               
               
           
         
       
     
     
         37 . A pharmaceutical composition comprising a compound of any of  claims 1 - 18  or  22 - 36  and a pharmaceutically acceptable carrier, excipient, or binder.